Retinoic Acid Improves Incidence and Severity of Necrotizing Enterocolitis by Lymphocyte Balance Restitution and Repopulation of LGR5+ Intestinal Stem Cells

Abstract

Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal disease of the premature infant. We have recently shown that NEC development occurs after an increase in proinflammatory CD4+Th17 (Th17) cells and reduced anti-inflammatory Foxp3+ regulatory T cells (Tregs) to the premature small intestine of mice and humans, which can be experimentally reversed in mice by administration of all-trans retinoic acid (ATRA). We have also shown that NEC is characterized by apoptosis of Lgr5-positive intestinal stem cells (ISCs–Lgr5+cells) within the crypts of Lieberkühn, which are subsequently essential for intestinal homeostasis. We now hypothesize that the normal lymphocyte balance within the lamina propria of the intestine can be achieved via administration of ATRA which restores mucosal integrity by preventing the loss of intestinal stem cells. Utilizing both in vivo and in vitro strategies we now demonstrate that Th17 recruitment and Treg depletion lead to increased apoptosis within ISC niches, significantly impairing proliferative capacity and mucosal healing. ATRA exerted its protective effects by preventing T cell imbalance, ultimately leading to the protection of the ISC pool preventing the development of NEC in mice. These findings raise the exciting possibility that dietary manipulations could prevent and treat NEC by modulating lymphocyte balance and the ISC pool within the newborn small intestine.

Prolyl hydroxylase 2 silencing enhances the paracrine effects of mesenchymal stem cells on necrotizing enterocolitis in an NF-κB-dependent mechanism

“…3a), suggesting that the intestinal stem cells (ISCs) in the intestinal crypts were severely damaged. This finding was consistent with a report by Nino et al 19 showing that NEC is characterized by apoptosis of intestinal stem cells located at the bottom of the intestinal crypts. Compared to the NEC injury group, the degree of apoptosis in the small intestine epithelium 1, 4, and 7 days after the PHDMSC-CM treatment was significantly reduced in the NEC model.…”

“…Lgr5expressing cells are actively proliferating ISCs responsible for the maintenance of the intestinal epithelium. The loss of Lgr5 + ISC pools has been implicated in NEC pathophysiology as it can cause decreased capacity for intestinal epithelial tissue regeneration and renewal that is observed in NEC 19 . In this study, expression of the Lgr5 + ISCs was very scattered 3 days after the NEC injury, with only 1-2 Lgr5-positive cells located at the very bottom of the intestinal crypt.…”

Vitamin D ameliorates neonatal necrotizing enterocolitis via suppressing TLR4 in a murine model

“…By upregulating signal transducer and activator of transcription 3, TLR4 promoted the polarization of T cells toward CD3 + CD4 + IL-17 + profile, whereas it reduced Foxp3 + regulatory T cells (20). This finding had been observed both in enterocytes and Lgr5 + intestinal stem cells (21). Our study observed elevated expression of proinflammatory cytokines in NEC, including IL-17, that could be ameliorated by vitamin D. There might be several pathways leading to this change and inhibition of TLR4 should be one of them.…”

“…There might be other mechanisms of the intestinal-protective effect of vitamin D in NEC. Immunological disturbance was an important pathological basis for NEC (21,23), and vitamin D had long been regarded as an important immunological regulator. Thus, there was reason to believe that immunological regulation was possibly another way by which vitamin D suppressed NEC.…”

The Role of Glycosaminoglycans in Protection from Neonatal Necrotizing Enterocolitis: A Narrative Review

“…In particular, Th17 cells, characterized by production of the inflammatory interleukin 17A (IL-17A) cytokine, have been shown to be upregulated in both murine and human NEC, and are thought to play a role in intestinal barrier dysfunction [34]. In an experimental model of NEC, mice treated with all-trans retinoic acid (ATRA), an inhibitor of Th17 differentiation [78], showed lower levels of Th17 cells, increased populations of Tregs, and reduced NEC severity [34,79]. Interestingly, retinoic acid is produced endogenously by IECs, but this production is thought to be largely dictated by luminal commensal bacteria [80].…”